Multiple Organ Dysfunction Syndrome (MODS) in trauma patients is linked to a subset of trauma patients who develop global T cell anergy and are at highest risk of mortality and morbidity. Some trauma patients' T lymphocytes become unresponsive (anergic), then recover from anergy but others do not perhaps because their anergic T cells are actively maintaining their anergy, thereby increasing their risk of MODS. We hypothesize that the subset of trauma patients who develop MODS and experience long-term T cell global anergy activate a repertoire of inhibitory signaling pathways actively perpetuating their T cell anergy. We also postulate that altered receptor expression is both causal and/or typical of these long-term anergic and anergy inducing T cells. We further contend that multiple different pathways of T cell anergy can occur post- injury and that these anergy inducing triggers will act through defined but characteristically different inhibitory block in signal transduction pathways critical to T cell activation and cytokine production. Three recently described long-term anergy- inducing, T cell signaling pathways have been targeted for investigation based on our preliminary patient T cell data. Reduced CD28 co-stimulation during activation through T cell receptor complex (TCR); Failed T cell downregulation of CTLA4 expression resulting in CTLA4 triggering of negative signaling; Upregulation of T cell inhibitory receptors activating SHP-1 phosphatase with consequent dephosphorylation of critical TCR associated phosphotyrosine kinases (PTK). Our Specific Aims are: 1) Determine if known T cell inhibitory signaling pathways are activated in trauma patients' anergic T cells and corresponds to prolonged anergy and increasing Marshall's MODS scores. 2) Delineate if reversal of post-trauma T cell anergy by exogenous cytokines and/or exogenous co-stimulation varies depending on the mechanisms of anergy induction. 3) Determine if patients' anergic T lymphocytes actively immunosuppress normal T lymphocyte activation or mediate Dendritic cell (DC) dysfunction disrupting both T cell immune function and monocyte/macrophage inflammatory/immunostimulatory balances thereby pivotally contributing to post trauma pathology.